TAK-960 - CAS 1137868-52-0
Catalog number: 1137868-52-0
Category: Inhibitor
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Polo-like Kinase (PLK)
TAK-960 is an orally available PLK1 inhibitor with potential antineoplastic activity. Polo-like kinase 1 inhibitor TAK-960 selectively inhibits PLK1, inducing selective G2/M cell-cycle arrest followed by apoptosis in a variety of tumor cells while causing reversible cell-cycle arrest at the G1 and G2 stages without apoptosis in normal cells. PLK1 inhibition may result in the inhibition of proliferation in PLK1-overexpressed tumor cells. PLK1, named after the polo gene of Drosophila melanogaster, is a serine/threonine kinase crucial in the regulation of mitosis.
TAK 960; TAK960
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Millennium Pharmaceuticals, Inc./Takeda Pharmaceutical Company Limited
1.PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase.
Inoue M1,2, Yoshimura M1, Kobayashi M1,2, Morinibu A1,2, Itasaka S1, Hiraoka M1, Harada H1,2,3,4. Sci Rep. 2015 Oct 27;5:15666. doi: 10.1038/srep15666.
The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960.
2.Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression.
Nair JS1, Schwartz GK1. Cell Cycle. 2015;14(19):3101-11. doi: 10.1080/15384101.2015.1078033.
Sarcomas are rare cancers and the current treatments in inoperable or metastatic disease have not been shown to prolong survival. In order to develop novel targeted therapies, we tested the efficacy of polo-like kinase 1 (PLK-1) inhibitor (TAK-960) in sarcoma. All the sarcoma cell lines were sensitive to TAK-960 with IC50s in the low nanomolar range. We chose MPNST, CHP100 and LS141 for our studies and of which MPNST cells exclusively underwent polyploidy after a delay in mitosis for about 18 hours; CHP100 cells, after a 24h mitotic delay, died of apoptosis; LS141, after a delay in mitosis stayed at 4N with mild apoptosis. Apoptosis induced by TAK-960 in CHP100 was associated with down-regulation of Mcl-1 and the effect was recapitulated by down-regulating PLK1 by siRNA, confirming that the effect of TAK-960 on Mcl-1 expression is target specific. With suppression of Mcl-1 by siRNA, TAK-960 induced apoptosis in MPNST cells as well. These effects were confirmed in vivo, such that TAK-960 more effectively inhibited CHP100 than MPNST xenografts.
3.Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1).
Nie Z1, Feher V, Natala S, McBride C, Kiryanov A, Jones B, Lam B, Liu Y, Kaldor S, Stafford J, Hikami K, Uchiyama N, Kawamoto T, Hikichi Y, Matsumoto S, Amano N, Zhang L, Hosfield D, Skene R, Zou H, Cao X, Ichikawa T. Bioorg Med Chem Lett. 2013 Jun 15;23(12):3662-6. doi: 10.1016/j.bmcl.2013.02.083. Epub 2013 Feb 27.
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.
4.TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens.
Hikichi Y1, Honda K, Hikami K, Miyashita H, Kaieda I, Murai S, Uchiyama N, Hasegawa M, Kawamoto T, Sato T, Ichikawa T, Cao S, Nie Z, Zhang L, Yang J, Kuida K, Kupperman E. Mol Cancer Ther. 2012 Mar;11(3):700-9. doi: 10.1158/1535-7163.MCT-11-0762. Epub 2011 Dec 21.
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G(2)-M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC(50) values ranging from 8.
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CAS 1137868-52-0 TAK-960

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